The long-term goal of this study is to improve colonoscopic performance via a novel optical technology. While colonoscopy is the "gold standard" for colorectal cancer (CRC) screening, the concern over missed lesions (~25% of adenomas and ~4-5% of carcinomas) results in overly frequent and hence unproductive colonoscopies. This squanders the finite endoscopic capacity thereby depriving many subjects from undergoing this potentially life-saving procedure. Our team has recently developed a novel optics technology which allows probing of the sub-epithelial microvasculature with unprecedented accuracy. Using this approach, we have reported, for the first time, that early colon carcinogenesis is accompanied by the early increase in mucosal blood supply (EIBS) that is present not only in a precancerous lesion itself (e.g. adenomatous polyp) but also in endoscopically and histologically normal mucosa surrounding the lesion. EIBS appeared to be an early marker of the "field carcinogenesis". This was confirmed in both animal models and in vivo human studies. EIBS was the most pronounced in the colonic segment (~1/3 of colon) that harbored neoplasia and the magnitude mirrored the proximity to the lesion. Based on these observations, we hypothesize that real-time EIBS assessment will improve colonoscopic neoplasia detection. We propose to determine threshold levels of microvascular blood content for discrimination of colonic segments that harbor neoplasia. We will optimize algorithms to adjust for confounding effects of factors such as age, gender, smoking, colonic region, etc. Finally, we will rigorously assess EIBS guidance benefit by performing a parallel (EIBS-aided vs. conventional) colonoscopy study. Miss rates for conventional and EIBS- aided colonoscopy will be compared. We believe that the clinical application will allow the endoscopist to rapidly determine whether a colonic segment harbors neoplasia. We believe that EIBS-guided colonoscopy will reduce adenoma miss rate leading to better clinical outcomes, fewer wasted follow up colonoscopies and hence more capacity for primary population screening. PUBLIC HEALTH RELEVANCE: The proposed work aims to decrease the neoplasia miss rate of colonoscopy. The methodology takes advantage of a novel biological effect: increased microvascular mucosal blood supply that is expressed in a colonic segment harboring neoplasia. This increased blood supply can be detected via a colonoscopically-compatible fiber-optic probe during colonoscopy to identify colonic segments that are most likely to harbor adenomas and, thus, guide colonoscopy. The major public health benefits are expected to be the improved detection of precancerous colonic lesions during colonoscopy.